Many viral proteins contain several, different domains that function at different steps during a virus infection. This is certainly true of the precursor to protein VI, pVI, and of its proteolytically processed product, protein VI, of adenovirus which are involved both early and late in infection. Early in infection, virus particles engage in a stepwise disassembly program coordinated in time and space during entry into cells leading to the delivery of the viral genome into the nucleus for replication. Protein VI is involved in endosome disruption. Late in infection, new virus particles are assembled and rendered infectious. pVI interacts with DNA to activate the adenovirus proteinase (AVP) and with hexon, the major structural proteins of adenovirus, to escort hexon into the nucleus.
Adenoviruses cause epidemic, endemic or sporadic disease and viremia, and are prevalent in the environment. They also cause fatal infections in immunosuppressed individuals. Adenovirus virions are assembled in part from precursor proteins. Of the 12 major virion proteins, 6 are precursor proteins in the young virion, an assembly intermediate.
Late in an adenovirus infection, the viral proteinase (AVP) becomes activated to process virion precursor proteins used in virus assembly. AVP is activated by pVIc, an 11-amino acid peptide from the C-terminus of the precursor protein pVI.
The high concentration of DNA inside the virion drives all the precursor proteins proteins and AVP onto the DNA by mass action. For AVP-pVIc complexes, the DNA-bound state predominates by at least one hundred thousand-fold over free AVP. This, in combination with the sieving action of the dense DNA, diminishes AVP's effective three-dimensional diffusion constant by at least one million-fold. Given these circumstances, a question is by what mechanism can vital bimolecular associations occur when both enzymes and substrates are essentially irreversibly bound to a fixed matrix, the viral DNA.
A model postulated that AVP-pVIc complexes slide along the viral DNA to locate and process the virion precursor proteins. In infectious wild-type virus, pVIc is covalently attached to AVP, indicating that the AVP-pVIc complex is the form of AVP that processes the virion precursor proteins.
Peptides with rapid sliding activity along DNA have the potential to considerably expand the biochemical repertoire of biological systems and offer the possibility of new regulatory mechanisms based on localization to and transport along regions of the genome. Such mechanisms have the potential to feed back on the cell state in many ways, including the variable quantity of DNA in the cell over the course of the cell cycle, its physical configuration within the cell, and its epigenetic state. The extent to which one-dimensional biochemistry extends beyond nucleic acid metabolism in nature is unknown beyond the initial example Applicants illustrate here in adenovirus. However, based on the discovery of human peptides with sliding activity, the possibility cannot be ignored.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.